Unknown

Dataset Information

0

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.


ABSTRACT: Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.

SUBMITTER: Bowling EA 

PROVIDER: S-EPMC8635244 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4569194 | biostudies-literature
| S-EPMC4303459 | biostudies-other
| S-EPMC5995333 | biostudies-literature
| S-EPMC5582957 | biostudies-literature
| S-EPMC7487859 | biostudies-literature
| S-EPMC8497895 | biostudies-literature
| S-EPMC3127435 | biostudies-literature
| S-EPMC4436509 | biostudies-literature
| S-EPMC8581040 | biostudies-literature
| S-EPMC5464546 | biostudies-other